Submissions for variant NM_003977.4(AIP):c.571C>T (p.Arg191Cys)

gnomAD frequency: 0.00001  dbSNP: rs189861025

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001024451	SCV001186470	likely benign	Hereditary cancer-predisposing syndrome	2022-09-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001061657	SCV001226406	uncertain significance	not provided	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 191 of the AIP protein (p.Arg191Cys). This variant is present in population databases (rs189861025, gnomAD 0.03%). This missense change has been observed in individual(s) with primary hyperparathyroidism (PMID: 35586626). ClinVar contains an entry for this variant (Variation ID: 825923). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AIP protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV001104757	SCV001261643	benign	Somatotroph adenoma	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Baylor Genetics	RCV001104757	SCV004195893	uncertain significance	Somatotroph adenoma	2024-03-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001061657	SCV005396606	uncertain significance	not provided	2024-05-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with primary hyperparathyroidism (PMID: 35586626); This variant is associated with the following publications: (PMID: 35586626)